Process for the manufacture of 1,2-benzisoxazole-3-methanesulphonamide

Abstract

The present invention provides an improved process for the preparation of 1,2-Benzisoxazole-3-methanesulphonamide (Zonisamide), an anti-epileptic agent having anti-convulsant and anti-neurotoxic effects. In another aspect, the invention provides a key intermediate, 1,2-benzisoxazole-3-methane sodium sulfonate (BOS-Na:NaCl), isolated as a crystalline sodium chloride associated compound. The BOS-Na:NaCl isolated is directly converted to Zonisamide using a controlled molar ratio of chlorosulfonic acid to avoid conversion to the disulfonated side products.

1 . A process for the manufacturing a compound of Formula I  
     
       
         
         
             
             
         
       
       comprising:  
       (a) subjecting a compound of the Formula II  
       
         
           
           
               
               
           
         
       
       to a chlorination reaction with a chlorinating agent, followed by an amidation reaction; and  
       (b) isolating the 1,2-benzisoxazole-3-methanesulphonamide compound of formula I.  
     
   
   
       2 . The process of  claim 1 , wherein chlorinating agent is phosphorous oxychloride.  
   
   
       3 . The process of  claim 1 , wherein the temperature for the chlorination reaction is from about 60 to about 90° C.  
   
   
       4 . The process of  claim 1 , wherein the reaction time for the chlorination reaction is from about 4 to about 12 hours.  
   
   
       5 . The process of  claim 1 , wherein the excess of phosphorous oxychloride is removed by vacuum distillation.  
   
   
       6 . The process of  claim 1 , wherein the amidation reaction is carried out in an organic solvent.  
   
   
       7 . The process of  claim 6 , wherein the organic solvent is an aliphatic ester.  
   
   
       8 . The process of  claim 7 , wherein the aliphatic ester is ethyl acetate.  
   
   
       9 . The process of  claim 1 , wherein anhydrous ammonia gas is used for the amidation reaction.  
   
   
       10 . The process of  claim 1 , further comprising re-crystallizing the 1,2-benzisoxazole-3-methanesulphonamide from step (b) in a protic solvent.  
   
   
       11 . The process of  claim 10 , wherein the protic solvent is methanol.  
   
   
       12 . The process of  claim 11 , wherein the re-crystallized 1,2-benzisoxazole-3-methanesulphonamide is greater than about 99% purity.  
   
   
       13 . A process for the preparation of 1,2-benzisoxazole-3-methane sodium sulphonate:sodium chloride having Formula II:  
     
       
         
         
             
             
         
       
       comprising,  
       (a) reacting 4-hydroxycoumarin with hydroxylamine hydrochloride in the presence of a base to provide 1,2-benzisoxazole-3-acetic acid; and  
       (b) reacting the 1,2-benzisoxazole-3-acetic acid with a chlorosulfonic acid complex to provide 1,2-benzisoxazole-3-methane sodium sulphonate:NaCl.  
     
   
   
       14 . The process of  claim 13 , further comprising the step of converting the 1,2-benzisoxazole-3-methane sodium sulphonate:NaCl to 1,2-benisoxazole-3-sulfonamide.  
   
   
       15 . The process of  claim 13 , wherein the base is sodium methoxide.  
   
   
       16 . The process of  claim 13 , wherein the reaction of step (a) is carried out in methanol.  
   
   
       17 . The process of  claim 13 , wherein the chlorosulfonic acid complex is a complex of chlorosulfonic acid and 1,4-dioxane.  
   
   
       18 . The process of  claim 17 , wherein the molar ratio of 1,2-benzisoxazole-3-acetic acid and chlorosulfonic acid complex is from about 1 to about 3.  
   
   
       19 . The process of  claim 18 , wherein the molar ratio of 1,2-benzisoxazole-3-acetic acid and chlorosulfonic acid complex is from about 1 to about 2.  
   
   
       20 . The process of  claim 13 , wherein the reaction of step (a) is carried out in a halo-aliphatic solvent.  
   
   
       21 . The process of  claim 20 , wherein the halo-aliphatic solvent is dichloroethane.  
   
   
       22 . The process of  claim 17 , wherein the reaction time is from about 2 to about 10 hours.  
   
   
       23 . The process of  claim 22 , wherein reaction temperature is the reflux temperature of the solvent.  
   
   
       24 . The process of  claim 13 , further comprising isolating the 1,2-benzisoxazole methane sulphonic acid sodium salt (BOS-Na) from a mixture of water and acetone.  
   
   
       25 . The process of  claim 24 , wherein 1,2-benzisoxazole methane sulphonic acid sodium salt is associated with sodium chloride (BOS-Na:NaCl).  
   
   
       26 . The process of  claim 25 , wherein the BOS-Na:NaCl is isolated in crystalline form having an HPLC purity greater than 95%.  
   
   
       27 . The process of  claim 26 , wherein crystalline BOS-Na:NaCl is characterized by an X-Ray powder diffraction (XRD) having the peaks at about 11.420, 13.400, 14.400, 14.720, 16.300, 18.520, 18.820, 19.720, 22.180, 22.520, 22.920, 23.900, 24.260, 25.620, 26.560, 27.220, 27.660, 28.780, 29.160, 29.660, 29.960, 31.120, 31.700, 32.040, 32.920, 33.400, 34.180, 34.680, 35.200, 36.460, 37.180, 37.500, 38.220 and 38.860±0.2 degree two theta.  
   
   
       28 . The process of  claim 26 , wherein the product has an Infra Red Spectroscopy (IR) spectrum having peaks at about 3322.34, 3165.79, 3084.01, 2990.54, 2946.34, 1564.32, 1516.68, 1384.28, 1339.46, 1151.50, 1131.93, 936.72, 916.78, 869.08, 763.46, 747.39, 660.45 and 557.83 cm −1 .  
   
   
       29 . The process of  claim 14 , wherein the BOS-Na:NaCl is used directly after isolating from step (b) of  claim 13.